Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor–Biased Ligand in Adults With COVID-19
Authors: Wesley H. Self, Matthew S. Shotwell, Kevin W. Gibbs, Marjolein de Wit, D. Clark Files, Michelle Harkins, Kristin M. Hudock, Lisa H. Merck, Ari Moskowitz, Krystle D. Apodaca, Aaron Barksdale, Basmah Safdar, Ali Javaheri, Jeffrey M. Sturek, Harry Schrager, Nicole Iovine, Brian Tiffany, Ivor S. Douglas, Joseph Levitt, Laurence W. Busse, Adit A. Ginde, Samuel M. Brown, David N. Hager, Katherine Boyle, Abhijit Duggal, Akram Khan, Michael Lanspa, Peter Chen, Michael Puskarich, Derek Vonderhaar, Lokesh Venkateshaiah, Nina Gentile, Yves Rosenberg, James Troendle, Amanda J. Bistran-Hall, Josh DeClercq, Robert Lavieri, Meghan Morrison Joly, Michael Orr, Jill Pulley, Todd W. Rice, Jonathan S. Schildcrout, Matthew W. Semler, Li Wang, Gordon R. Bernard, Sean P. Collins, Richard C. Becker, Gregory del Zoppo, Peter Henke, Richard Holubkov, Maryl Johnson, Kim Kerr, Hannah I. Lipman, Fedor Lurie, Bertram Pitt, Sara K. Vesely, Jerome L. Fleg, Dave Aamodt, J'Mario Ayers, Debra Clark, Jessica Collins, Maya Cook, Sheri Dixon, John Graves, Courtney Jordan, Christopher J. Lindsell, Itzel Lopez, David McKeel, Dirk Orozco, Nelson Prato, Ally Qi, Madiha Qutab, Christa Stoughton, Krista Vermillion, Kelly Walsh, Stephanie Winchell, Taylor Young, Richard Franklin, Elizabeth Wagner, Thomas Walther, Mark Demitrack, Jakea Johnson, Ryan Walsh, Brian Bales, Karen Miller, Donna Torr, Harsh Barot, Leigha Landreth, Mary LaRose, Lisa Parks, J. Pedro Teixeira, Sandra Cardenas, Juan A. Ceniceros, Amy G. Cunningham, Susan Kunkel, Debbie M. Lovato, Brooklin Zimmerman, Thanh Nguyen, Wesley Zeger, Heather Nichols, Noah Wiedel, Ali Javaheri, Stephanie Stilinovic, Carolyn Brokowski, Jing Lu, Muriel Solberg, Dana Lee, Kristopher Roach, Brian Tiffany, Charlotte Tanner, Annette Taylor, Jennine Zumbahl, Aamer Syed, Jessica Mason, Patrick E. H. Jackson, Rachael W. Coleman, Heather M. Haughey, Kartik Cherabuddi, Nastasia James, Rebecca Wakeman, Christopher Duncan, Cynthia Montero, Angela J. Rogers, Jennifer G. Wilson, Rosemary Vojnik, Cynthia Perez, David Wyles, Terra D. Hiller, Judy L. Oakes, Ana Z. Garcia, Michelle Gong, Amira Mohamed, Luke Andrea, Rahul Nair, William Nkemdirim, Brenda Lopez, Sabah Boujid, Martha Torres, Ofelia Garcia, Flora Martinez, Amiran Baduashvili, Jill Bastman, Lakshmi Chauhan, David J. Douin, Lani Finck, Ashley Licursi, Caitlin ten Lohuis, Sophia Zhang, William Bender, Santiago Tovar, Sharon Hayes, Nicholas Kurtzman, Elinita Rosseto, Douglas Scaffidi, Nathan Shapiro, Jonathan Pak, Gopal Allada, Genesis Briceno, Jose Peña, Minn Oh, Harith Ali, Sasha Beselman, Yolanda Eby, Vitaliy Klimov, R. Duncan Hite, Hammad Tanzeem, Chris Droege, Jessica Winter, Susan Jackman, Antonina Caudill, Emad Bayoumi, Ethan Pascual, Po-En Chen, Simon Mucha, Nirosshan Thiruchelvam, Matthew Siuba, Omar Mehkri, Brian E. Driver, Audrey F. Hendrickson, Olivia R. Kaus, Christina Ontiveros, Amy Riehm, Sylvia Laudun, Debra Hudock, Christopher Ensley, Valerie Shaner, Nina Gentile, Derek Isenberg, Hannah Reimer, Paul Cincola, Estelle S. Harris, Sean J. Callahan, Misty B. Yamane, Macy AG Barrios, Neeraj Desai, Amit Bharara, Michael Keller, Prat Majumder, Carrie Dohe, Jeanine D’Armiento, Monica Goldklang, Gebhard Wagener, Laura Fonseca, Itzel Valezquez-Sanchez, Nicholas J. Johnson, Emily Petersen, Megan Fuentes, Maranda Newton, Stephanie Gundel, Vasisht Srinivasan, Tessa Steel, Bryce Robinson
Journal: JAMA (2023)

Importance Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor–biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient’s status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, −2.3 [95% CrI, −4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, −2.4 [95% CrI, −5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration ClinicalTrials.gov Identifier: NCT04924660